2-47806751-CTTTTTTTTTTTTTTT-CTTTTTTTTT

Variant names:

• chr2-47806751-CTTTTTT-C
• rs59056100
• NM_000179.3:c.4002-15_4002-10delTTTTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000179.3(MSH6):​c.4002-15_4002-10delTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000831 in 1,444,692 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). The gene MSH6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000070 (2 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.36
• Publications: 0 publications found

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

FBXO11 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for MSH6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-47806751-CTTTTTT-C is Benign according to our data. Variant chr2-47806751-CTTTTTT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2442867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000202 (28/138448) while in subpopulation AMR AF = 0.000957 (13/13588). AF 95% confidence interval is 0.000565. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.4002-15_4002-10delTTTTTT		intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.4098-15_4098-10delTTTTTT		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.4008-15_4008-10delTTTTTT		intron	N/A	NP_001393742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.4002-15_4002-10delTTTTTT		intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*3349-15_*3349-10delTTTTTT		intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.4029-15_4029-10delTTTTTT		intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 29 AN: 138394 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000958

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000471

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.0000313

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000704 AC: 92 AN: 1306244 Hom.: 2 AF XY: 0.0000721 AC XY: 47 AN XY: 652176

African (AFR) AF: 0.000285 AC: 8 AN: 28098

American (AMR) AF: 0.000329 AC: 12 AN: 36428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24240

East Asian (EAS) AF: 0.000116 AC: 4 AN: 34568

South Asian (SAS) AF: 0.000118 AC: 9 AN: 75958

European-Finnish (FIN) AF: 0.0000233 AC: 1 AN: 42874

Middle Eastern (MID) AF: 0.00444 AC: 23 AN: 5178

European-Non Finnish (NFE) AF: 0.0000239 AC: 24 AN: 1004650

Other (OTH) AF: 0.000203 AC: 11 AN: 54250

GnomAD4 genome AF: 0.000202 AC: 28 AN: 138448 Hom.: 0 Cov.: 0 AF XY: 0.000224 AC XY: 15 AN XY: 66846

African (AFR) AF: 0.000236 AC: 9 AN: 38070

American (AMR) AF: 0.000957 AC: 13 AN: 13588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3320

East Asian (EAS) AF: 0.00 AC: 0 AN: 4408

South Asian (SAS) AF: 0.000473 AC: 2 AN: 4228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7960

Middle Eastern (MID) AF: 0.00741 AC: 2 AN: 270

European-Non Finnish (NFE) AF: 0.0000313 AC: 2 AN: 63834

Other (OTH) AF: 0.00 AC: 0 AN: 1900

Alfa AF: 0.00 Hom.: 174

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs59056100; hg19: chr2-48033890;